Dawn Laney, MS, CGC, Associate Professor/Genetic Counselor. Review of relevant definitions for Fabry disease. Review of genetics for Fabry disease. Review of diagnosis of Fabry disease. Review of treatment for Fabry disease. Review of research for Fabry disease.

1. Fabry 101
Dawn Laney, MS, CGC
Assistant Professor/Genetic Counselor
Department of Human Genetics
Emory University

2. YOU are the Expert!
For Internal Training Only. Do Not
Distribute.
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3. Important Background Pieces

4. • Defining Fabry terms
• Causes of Fabry disease
• How Fabry disease runs in families
• Diagnosis
• Treatment
• Research
What Are We Going to Talk About?

5. Definitions
Cells: The basic building block that makes up our
body. There are different types such as:
Endothelial cells: the cells that line the inside of
blood vessels in body heart/kidney/brain/etc.
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6. Definitions
Lysosome: The recycling center of the cell
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7. Definitions
• Gene: The instructions for the body lined
up on chromosomes like beads on a string.
• GLA: A gene on the “X” chromosome that
makes alpha-galactosidase A. Changes or
mutations in GLA make alpha-gal not work.
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8. Standard gene: CAT CAG AAT GAG
Missense mutation: CAT CAG ATT GAG
Nonsense mutation: CAT TAG
Insertion: CAT CAG AAA TGA G…
Deletion: CAT CAG AAT GAG
Duplication: CAT CAG CAG AAT GAG
Frame Shift: CAT GAG AAT CAG
Splice Site: CAT GAG 8
Types of GLA Mutations:
A reminder note about hair balls

9. Definitions
• Enzyme: “Scissors” made of protein that
break down molecules. Can be in the
lysosome.
• Alpha-galactosidase A (“alpha-gal”): An
enzyme in the lysosome that breaks down
products
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10. Definitions
Globotriaosylceramide (GL-3/Gb3) and Lyso-
Globotriaosylceramide (lyso-GL-3/Gb3)
Aka “GUNK” that can’t break down without
working alpha-gal
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11. Gunk affecting the Blood Vessels
• Storage narrows all blood vessels as cells
are full of GL3 lining the walls
• The storage of GL3 also “irritates” the cell
leading to inflammation and cell death
throughout the body.

12. So putting all together
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13. Fabry Disease: Key things
• Storage begins before birth.
• Symptoms can be very different between affected
people in a family.
• Damage is progressive, you have to watch
symptoms as they change over time

14. Fabry Disease: Key things
• Women with Fabry disease are NOT just carriers.
• Females are at high risk for major organ
involvement (about 2/3 lifetime risk).
• They need monitoring and treatment
• Women are complicated:
-X-inactivation/lyonization

15. Fabry Disease: More important
things
There are multiple forms of Fabry disease:
• “Classic” Fabry disease
• “Non-classic” Fabry disease (also called
variant or later onset or attenuated or type 2)
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16. Classic
Fabry
Disease
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17. Non-Classic Fabry Disease
• One term for a lot of variety
– All Fabry disease symptoms, just later
– Mainly heart disease
– Mainly kidney disease
– Etc.

18. Fabry Disease: Diagnosis
• Enzyme assay
– Blood cells called Leukocytes most often used
for measuring enzyme levels
– markedly deficient in affected males, >30% of
females have normal levels
• Genetic Testing: Sequencing, familial
mutation, deletion/duplication
– Important for diagnosis of females
– Can help understand disease onset
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19. What’s the Difference?
• Sequencing: Spell checking the whole
GLA gene
• Deletion/duplication: Checking for
“words” added or missing to the whole
GLA gene
• Familial mutation: ONLY checking to
see if one “word” is misspelled in the
GLA gene
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20. Reminder: Genetics of Fabry disease
• Over 600 known mutations in GLA. Different
types of mutations: duplications, deletions,
inversions, nonsense, splice sites, and missense
(www.hgmd.cf.ac.uk/ac/index.php)
• The vast majority of GLA mutations in the Fabry
population are novel and family specific.
• Makes is hard to match gene change to symptoms
expected.

21. Other diagnosis: Newborn
Screening for Fabry disease (in the
United States)
• Mainly detects males with Fabry disease as the
test is enzyme only. BUT 60% females should be
detected too.
• Not everywhere in the United States
– Missouri, Illinois, Tennessee, Pennsylvania (optional)
– Pilot project at Mt. Sinai in NYC
- Soon…New Jersey, New Mexico

22. Laney et al, JGC, 2013

23. When you find one
individual affected by
Fabry disease, on average
5 of their family members
are affected
Laney et al, J Genet Couns. 2008 Feb;17(1):79-83.

24. X-Linked Inheritance
1. Men with Fabry disease will always have unaffected
sons and heterozygote daughters
2. Women with Fabry females have a 50% risk with
each pregnancy of passing on the abnormal gene to
both sons and daughters
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25. http://www.fabrycommunity.co
m/Healthcare/About/Genetics.a

26. Enzyme Replacement Therapy
• Fabrazyme (agalsidase beta) from Genzyme-Sanofi
– r-hGAL produced in CHO cells
– dose: 1 mg/kg every other week
• Replagal (agalsidase alpha) from Shire
– R-hGAL produced in human fibroblasts
– dose: 0.2 mg/kg every other week
• Unigal (Pegunigalsidase alpha or PRX-102) from
Protalix
– Clinical trials currently to make sure safe and effective

27. ERT/Fabrazyme

28. Mean Capillary Endothelium Scores
As FabrazymeTreated Population
(Scale 0-3)
Placebor-hGAL
Baseline Week 20
0
1
2
3
Kidney
Skin
Heart
Baseline Week 20
0
1
2
3
Kidney
Skin
Heart
kidney p < 0.0001
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29. Pre-treatment Post-treatment
Primary Endpoint
GL-3 Is Cleared From Peritubular Capillary Endothelium
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30. Post-treatment
Pre-treatment
GL-3 Levels Are Reduced in Podocytes
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31. What can we expect from ERT?
Arrest or slower progression vs. reversal
• Can’t reverse scarring
• Decreases pain in some over time
• Decreases GI symptoms in most over time
• Slows down renal progression, may prevent renal
disease if treatment begun early
• Improves QoL and fatigue in many
• Reduces mild LVH, prevents progression if there is no
scarring
• No major effects on stroke risk when strokes have
occurred started in adulthood
• No major effects on the ears
• How much can be prevented if treatment is started before
symptoms begin?
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32. • Boys have renal pathology on biopsy: storage in cells,
foot-process effacement, glomerulosclerosis (Tøndel et al, Am J
Kidney Dis 51:767-776, 2008; Najafian et al, Kidney Int 79:663-70, 2011)
• Podocytes cannot be cleared in adults (phase III ERT
data), but can be cleared in children (Tøndel et al, J Am Soc
Nephrol 24:137-148, 2013)
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33. Important to Know: From FD Registry
• Patients who had “severe events” while on
ERT had significantly more advanced
kidney/heart disease when they started ERT
• Patients who started ERT younger had less
risk of on ERT “severe events”
• Of patients with no “serious events” before
starting ERT: 84% males; 92% females
remained event free
• Of pts with pre-ERT events, 65% didn’t
experience another one while on ERT
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Hopkin et al, Molecular Genetics and Metabolism, 2016

34. Infusion Associated Reactions
Not everyone has IARs, but if they do they are
treatable in almost every situation:
• During:
– First infusion: allergic to enzyme. Think
symptoms like person with a “peanut allergy”.
– 7-9th infusion: shaking, chills,
nausea/vomiting, etcl.
• After:
– Fatigue
– GI symptoms
– Headaches

35. Chaperone Therapy
• Galafold (Migalastat)
• Not Approved by FDA for use in US
• Oral Therapy
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36. Reduces GL-3/GB-3
Patients with amendable mutations who had
not been on therapy measured a ≥50%
reduction of the disease substrate GL-3 in the
interstitial capillaries of the kidneys following
6 months treatment with migalastat.
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37. How does it work?
Galafold works by stabilizing the body’s own
dysfunctional enzyme, so it can clear the
accumulation of disease substrate in patients
who have amenable mutations.
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38. 38

39. 39
“Normal” alpha-gal A enzyme
“Motorcycle”
“Amenable” alpha-gal A enzyme
“Electric bike”

40. “Normal” alpha-gal A enzyme
“Motorcycle”
“Non-amenable” alpha-gal A enzyme
“Unicycle”

41. Who Many Benefit
Those with Amenable GLA mutations that naturally
produce amendable forms of alpha-galactosidase A
that can be “helped” by the medication (about 60%
of people living with Fabry disease).
As far as we can tell from here: limitations similar
to ERT for those with an amenable mutations
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42. Treatment: Not just ERT &
Chaperone
– Treatment of daily burning pain
– Treatment of pain crises
– Treatment of protein in urine
– Treatment of diarrhea/constipation
– Treatment to decrease stroke risk
– Treatment of panic attacks/anxiety/depression
– Treatment for other causes of fatigue
– Treatment of edema (puffy ankles)

43. What are Guidelines?
• Monitoring and treatment recommendations
from the experts.
• You should know them, to make sure your
medical team is following them…Empower
yourself!

44. Fabry Registry
Recommended Schedule of Assessments > 18 yo

45. Fabry Registry Pediatric
Recommended Schedule of Assessments < 18 yo

46. Technological Advancements and
New knowledge
• May not be on the Fabry Registry schedule of
assessments
– Cardiac MRI
– Renal Biopsies
– Measured GFR
– DexA scans
– Psychiatric Assessment
– Additional biomarkers: Urine GL3, LysoGL3
– Vitamin D
– Other Patient Reported Outcomes
– Other Disease Severity Scale Measurements

47. Beyond Registry Recommendations
Often papers by specialty will have additional management
suggestions
– General: Eng 2006 revision in process.
– Cardiology: Weidemann F, et al. Orphanet J Rare Dis. 2013 Aug
6;8:116.
– Genetic Counseling: Laney et al, J Genet Couns. 2013
Oct;22(5):555-642013
– Infants: Laney et al, Genet Med. 2014 Sep 18.
– Nephology:
• Ortiz A, et al. Nat Clin Pract Nephrol. 2008 Jun;4(6):327-36.
• Warnock et al. J Am Soc Nephrol. 2014 Apr;25(4):653-5.
– Women: Wang et al. Genet Med. 2007 Jan;9(1):34-45.

48. You don’t have to read them, but
you should know what they say
Key people you need in your life:
- A good primary care doctor willing to learn
and then help you understand Fabry disease
- A relationship with a Center of Excellence
in Fabry disease
- Specialists for FD symptoms: kidney
doctor (nephrologist), heart doctor
(cardiologist), etc.

49. Future Treatments
• ERT + chaperone to increase cellular uptake in
more resistant cells (e.g. cardiomyocytes,
podocytes)
• Inhibit production of GL-3 (“substrate inhibition”)
+/- ERT (Genzyme)
• Implantable enzyme production (encapsulated
cellular bioreactors)
• Gene therapy (Canadian study/Avebio)

50. My Family Tree
dawn.laney@emory.edu
Dawn Laney dawn.laney@emory.edu

51. Gadolinium Enhanced Cardiovascular
MRI in Fabry Disease
(Moon et al., Eur Heart J 24:2151-2155, 2003)
Fabry has focal and diffuse scarring
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52. Females can have cardiac
scarring without hypertrophy
Niemann et al., J Am Coll Cardiol Img 4:592-601, 2011
For Internal Training Only. Do Not Distribute.
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53. Pregnancy?
1. If the woman is already pregnant:
Prenatal testing of at risk fetus
• Must have known family mutation in GLA
• Call lab genetic counselors to discuss
sample requirements WELL before day of
invasive testing .

54. • For parental reassurance if normal results
• To plan for birth of an affected child
• Financial planning
• Personal planning
• To allow for decisions about pregnancy
Why Consider
Prenatal Diagnosis?
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55. Prenatal Diagnosis
• DNA analysis via invasive testing:
• Choronic Villus Sampling (CVS) or
amniocentesis*
*labs will only do this testing if familial
mutation has already been identified
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56. Not Pregnant yet?
Additional Family Planning Options
• Pursue a pregnancy, with or without
prenatal testing.
• Test baby at birth
• Adoption
• Donor egg or donor sperm
• Preimplantation genetic diagnosis (PGD)
and in vitro fertilization (IVF)
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